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Similarities and differences between the novel H7N9 and H5N1 influenza A viruses
Ruben Donis, DVM, PhD
National Center for Immunization & Respiratory DiseasesInfluenza Division
Associate Director for Policy Evaluation and PreparednessInfluenza Division, NCIRD, Centers for Disease Control and Prevention
EMERGING VIRAL DISEASES – THE “ONE HEALTH” CONNECTIONForum on Microbial Threats, IOM, NAS
18‐19 March, 2014
Influenza A Virus
8 RNA genes HA: receptor binding,
fusion NA: virus release Evolution
• Error rate 10-4
o All possible changes in ~200,000 virions
• Genetic reassortment
HA NA
8 RNA genes
Host Species for HA and NA SubtypesH1
H2
H3
H4
H5
H6
H7
H8
H9H10 N10H11 N11H12
H13
H14
H15
H16H17
H18
N1N2
N3
N4
N5
N6
N7
N8
N9
Other Animals
Other Animals
Other Animals
Other Animals
Other Animals
Other Animals
Blue icons: lack of sustained transmission
Courtesy of Dr. Danielle Iuliano, Influenza Division
Human Cases Avian Influenza A (H7N9) March 13, 2014
†† Confirmed clusters are two or more confirmed cases of H7N9 that are close contacts of one another.
Cumulative counts by Report Date 30 Mar–30 Sept, 2013
1 Oct 2013– present Total
Countries affected China China, Malaysia
China,Malaysia
Number of provinces/municipalities/areas/SARs with confirmed cases – China
11 / 2 / 1 / 0 9 / 2 / 1 /1 13 / 2 / 1 / 1
Number of confirmed cases 135 254 389Number of confirmed cases hospitalized 131 253 384Number of fatal confirmed cases 45 79 124Cases of confirmed human to human transmission 0 0 0
Number of confirmed clusters†† 5 3 8Number of asymptomatic infections 1 0 1
• Most infections have caused severe disease, older adults– Limited evidence of mild illness, restricted to children
* Onset date unknown for 6 cases
0
2
4
6
8
10
12
14
2/18 3/18 4/18 5/18 6/18 7/18 8/18 9/18 10/18 11/18 12/18 1/18 2/18 3/18 4/18 5/18
Num
ber o
f Cases
Onset Date
Malaysia China
Epidemic Curve for Confirmed Cases of A(H7N9),18 Feb 2013 – 13 Mar 2014 (N=389)*
2013 2014
First wave Second wave
Courtesy of Dr. Danielle Iuliano, Influenza Division
22 new casesSince 2004:659 total cases/388 fatal
Human Cases Avian Influenza A (H5N1)September 17, 2013 - March 13, 2014
Cambodia Fatal
ChinaVietnamCanada
Indonesia
Oct Nov Dec Jan FebSept Mar
More than 10 human cases of H7N9 in China for each H5N1 case globally (in Asia and Africa)
Courtesy of Dr. Wenqing Zhang, WHO GISRS
Most cases had direct/close contact with poultry• Direct or indirect exposure to poultry
Most cases in urban centers• Exposed to poultry at live bird markets
Exposure historyo backyard poultry o live poultry markets
Difference in exposure reflects current patterns of H5N1 distribution in poultry populations• H5N1 more widespread in backyard poultry than H7N9
Human Cases of Avian Influenza A (H5N1) Virus
Human Cases of Avian Influenza A (H7N9) Virus
* Onset date unknown for 6 cases
0
2
4
6
8
10
12
14
2/18 3/18 4/18 5/18 6/18 7/18 8/18 9/18 10/18 11/18 12/18 1/18 2/18 3/18 4/18 5/18
Num
ber o
f Cases
Onset Date
Malaysia China
Epidemic Curve for Confirmed Cases of A(H7N9),18 Feb 2013 – 13 Mar 2014 (N=389)*
2013 2014
First wave Second wave
Live PoultryMarkets Close
Live PoultryMarkets Close
• Drastic drop in H7N9 cases after closure of live marketsCourtesy of Dr. Danielle Iuliano, Influenza Division
Closing the live bird markets
• HK 1997 H5N1: Human and avian cases fall to ~ zeroCourtesy of Dr. Rob Webster, St Jude Hospital.
(H5N1) Outbreak in Hong Kong, 1997The Role of LBMs
Close down the live bird market system• Only temporary solution
One clean day per month H9N2 fell to low levels, then increasedfailed
Additional clean daysfailed No overnight carry over ‐ daily all out
H5N1 and other subtypes eliminated
Lam TT et al. 2013 Nature
Genesis of H7N9 in China
• Since 2013, multiple reassortments with related H9N2 viruses
HA
Internal genes
NA
S - S
HA1 HA2
S - S
HA2Host Protease
HA0
HA Cleavage Site
HA1
HA cleavage is required for
virus infectivity
Cleavage site
Human Arg Glu Thr Arg . Gly
Low Path AvianH7N9
Arg Glu Thr Arg. Gly
Highly pathogenic H5 and H7 viruses Arg Arg Arg Arg . Gly H5N1
Multiple basic amino acids
Low Pathogenicity of H7N9 is “Subject to Change Without Notice”
H7N9 is a “low path” virus that can become highly pathogenic with a few mutations at cleavage site• When that happens, it is expected to resemble H5N1
Low Pathogenicity of H7N9 has Major Implications for Detection and Control
Detection• No H7N9 chicken die-offs as is the norm for H5N1• Human cases of H7N9 have been sentinels for virus detection in
poultry in China
Control• Consumer reaction to human H7N9 cases: buy pork!!
o Drop in retail price of chicken → economic loss to entire value chain o $16 B U.S. dollars loss in one year
Reference: http://www.caaa.cn/show/newsarticle.php?ID=329866]
Contact
Contact
Contact
Inoculated
Inoculated
Inoculated
Respiratory Droplet (RD)
Droplet Transmission of H7N9 and H5N1: Ferret Model
Human virus: 100% droplet transmission to contacts
H7N9 virus: ~30%
H5N1 virus: 0%
Belser J et al 2013, Nature. Chen HL et al 2013; Richard M, et al. Nature. 2013, 501(7468):560‐3
Molecular Basis of Inefficient Droplet Transmission of H7N9
Courtesy of Doug Jordan, Influenza Division
HA Receptor Binding Preferences
Sialylated glycan ReceptorAvian-like Human-like
VirusHuman Minimal StrongH5N1 Strong MinimalH7N9 Strong Moderate
Location Human Lung Human Nasal/Trachea
JCFM Dortmans et al. Scientific Reports 3, Article number: 3058 doi:10.1038/srep03058
H7N9: “dual” receptor specificity, but predominantly avian• Q226L and G186V mutations in HA
Differences in the Ecology of A(H5N1) and A(H7N9)
H5N1 Kaplan 2013 #3929; H7 Pantin‐Jackwood et al 2014, Ku et al. 2013
H5N1 H7N9
Unlike H5N1, H7N9• Transmits more efficiently among gallinaceous birds than ducks• No transmission to mammalian species or wild migratory birds
Kilpatrick AM Proc Natl Acad Sci U S A. 2006 Dec 19;103(51):19368‐73. Epub 2006 Dec 7.
Spread of A(H5N1): 2003‐2005Purple circles= wild bird spread
• If H7N9 becomes transmissible in wild migratory birds, it will likely spread to many countries
A Reservoir of H5N1 and H7N9 In Siberia?
Wintering
Breeding
Frozen lakes in Siberia serve as virus reservoirs
Conclusions A(H5N1) vs. (H7N9)
Similarities:• Both viruses acquired “internal” genes from H9N2 • Neither established sustained circulation in swine or other
mammals• No reassortment with swine or human viruses• Share reservoirs in gallinaceous birds• Hypercytokinemia correlated with more severe outcomes
Conclusions A(H5N1) vs. (H7N9)
Differences:• H5N1 HA multibasic cleavage site – absent in H7N9
o Lethal for gallinaceous poultry, H7N9 is subclinicalo H5N1 die-offs serve as sentinels for human infectionso H7N9 human infections are indicators of virus in poultry
• H5N1 binds avian-like receptor preferentiallyo Targets lower respiratory tract of humans
• H7N9 dual avian-human receptor binding specificityo Target both upper and lower respiratory tract
• H7N9 is partly droplet transmissible in ferrets, H5N1 is not• H7N9 appears to be more transmissible to humans than H5N1